BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder that impacts the quality of life of patients due to its progressive course, the demands of daily self-management, emotional burden and other subjective experiences. This study aimed to assess the self-management efficacy of patients with FD, identify influencing factors and examine the relationship between quality of life and self-management efficacy to support the development of personalized treatment plans. METHODS: A cross-sectional study was conducted from March to May 2024 involving 529 patients with FD in China. A clinical assessment tool: the Fabry Disease Self-Management Efficacy Questionnaire (F-SEQ) was developed. Structural validity, internal consistency and test-retest reliability were assessed. Logistic regression analysis was used to identify the factors associated with self-management efficacy. RESULTS: The finalized F-SEQ included 42 items and demonstrated good reliability and sensitivity to change. Self-management efficacy scores among patients were moderately low. The total F-SEQ score indicated significant correlations with both the General Self-Efficacy Scale (GSES) and the Study 36-Item Short Form Health Survey. Confidence in medication management was strongly correlated with GSES scores (p < 0.001). Higher levels of emotional and social management were significantly associated with better social function and reduced physical pain (p < 0.001). Compared to GSES, the F-SEQ total score showed a stronger correlation with social function and physical pain. CONCLUSION: The F-SEQ is a reliable and valid instrument for assessing self-management efficacy in patients with FD in the Chinese context. It also demonstrated stronger predictive associations with quality-of-life domains than conventional tools, supporting its use in informing personalized intervention strategies aimed at improving patient outcomes.